Pharmaceuticals



United States Patent r' PHARMACEUTICALS Dominic D. Micucci, Havertown, S'ouren Avakiah and Robert R. Brendel, Oreland, and Gustav J. Martin, Philadelphia, Pa., assignors to The National Drug Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Application March 28, 1957 Serial No. 649,015

3 Claims. (Cl. 260-294) This invention relates to and has for its object the provision of a novel series of chemical compounds and methods for their preparation, the compounds being useful as medicinals which affect the central nervoussystem and yield hypnotic orsedative-etfects. This ap lication is a continuation-in-part of Serial No. 539,679, filed- Octobrl 1955*, new abandoned, same inventors.

The compounds of the invention are those having the ge'ner al forinula 2,874,160 Patented Feb. 17, 1959 ice 2 pent'e'nyl'; and Y'is a member of the group consisting of methylene, oxygen and the bond forming a pyrrolidine ring and NH and NR" wherein R" is alkyl, alkenyl, aralkyl or carbalkoxy.

These compounds may be prepared by condensing the desired allyl, cyclopentyl or cyclopentenyl halide with a dialkyl malonate (or alkyl acetoacetate) in an anhydrous organic medium, such as alcohol or toluene, in the presence of equimolecular amounts of sodium, sodium alkbxide or sodium hydride condensing the resulting products with the desired alpha-phenylalkyl halide in a similar manner, hydrolyzing by refluxing in alcoholic KOH Q r'NaOI-I, etc.) to obtain the free acid, decarboxylating to obtain the substituted fatty acid and ultimately treatingit with-a halogehating agntsuch as SOCl or-PCl to obtain the acid halide. The acid halide may then be treatedwiththe desired amine. to form the final product. if the amine is piperaz ine, the acid halide istreated in an anhydrous organic'solventmedium with [thel carbo lower alkoxyxpiperazine-and the respltingj-produet is decar balkoxylated to formthe secondary amine, then treated further with the appropriate hydrocarbon halide (preferably alkyl, especially lower alkyl halide) to form the tertiary amine. When the amine is piper-idine or pyrrolidine, the free base is treated directly to obtain the tiesired product} This series of steps is graphically illustratedbelow (-R, R, W,-X and Y having the same mean 7 R'Br' cedar do on;

R GOOH w o'o'o'n l decarbor.

R coon than 0 nooom R H AEMON w l NCOOEt R Don-(Fools N H w IL.

rwx

Where the R group in the alpha-phenylalkyl halide is other than hydrogen, the hydrocarbon halide (R'X) must be reacted with the dialkyl-malonate prior to the condensation with the alpha-phenylalkyl halide when the reaction is carried out in alcohol. In toluene, however, these alkylation steps may be carried out in either order. This is possible because, in toluene, for instance, MeOH formed from the reaction of NaOMe and alpha-phenylalkyl-malonic ester is distilled out, hence shifting the equilibrium:

R NaOMe qi-HCHXO OzEt):

-JJHC(CO;Et)a]Na M90111 to the right eliminating the predominant RX+NaOMe reaction. When sodium or sodium hydride and toluene are used, the order of alkylation is also immaterial since no competing side reactions are involved.

In the cases where the substituents in the molecule are such that the carbon atoms alpha and beta to the carboxamide group are both asymmetric centers and dilferent, then there exists two isomeric dl pairs which may be separated by fractional crystallization.

Although it is desirable to use stoichiometric quantities of the reactants in the condensation, considerable variation is possible in each step. Likewise, other reaction conditions such as temperature, pressure and the inert solvents which are utilized, may be varied within wide limitations.

The compounds of the invention may be incorporated in the usual manner for ingestion, preferably by the oral route. Thus, the compounds may be tabletted or encapsulated; and, if desired, they may be made into suspensions, elixirs or other such liquid form. The dosage which is utilized will vary with the particular patient being treated. The dosage unit forms may, therefore, be conveniently made up to contain about 50-200 mg. (preferably about 50 mg.) per dosage unit, e. g. tablet, capsule, teaspoonful, etc. Tablets may, of course, be scored to provide for further fractional dosages.

Following are working examples presented as illustrative of the invention. However, these examples are not in any way limitative and cannot be construed as any restriction on the invention.

EXAMPLE 1 A. Preparation of allyl-p-xylylacetylchloride Diethyl malonate, 62.5 3., is added to a well-stirred O-CLH-fy-O ON suspension of 22.2 g. NaOMe in 250 ml. dry toluene. Then 55.0 g. p-xylylchloride are added dropwise over a period of two hours. The reaction mixture is heated for an additional two hours, cooled, acidified with an hydrous HCl and filtered through a diatomaceous earth filteraid. The filtrate is distilled, and the diethyl p-xylylmalonate product thus recovered in the amount of 60 g. (B. P. 112120 C.). This ester is then allylated in a similar manner using 200 ml. dry toluene, 13 g. NaOMe and 27.5 g. allyl bromide. (The MeOH formed is distilled from mixture.) Diethylallylp-xylyltnalonate, B. P. 118-123 C., is obtained in a yeld of 59 g. This is hydrolyzed with 59 g. KOH, 90 ml. H 0, and 59 ml. EtOH to obtain the diacid, which is then decarboxylated, treated with SOC1 and distilled. The allyl-p-xylylacetylch1oride product, B. P. 89-91 C., amounts to 26.5 g.

B. l-[allyl-p-xylylacetyl] -piperidine A solution of 24 g. allyl-p-xylylacetyl chloride in 50 ml. anhydrous ethyl ether is added dropwise to a stirred solution of 18 g. piperidine in 200 m1. anhydrous ethyl ether. The reaction mixture is stirred for 2 hours, allowed to stand over night and then filtered. The filtrate is washed several times with water, dried over anhydrous Na SO and distilled to obtain the desired amide (B. P. -162 C.).

Following the procedure of Example 1-B except that an equivalent amount of morpholine is substituted for the piperidine used in the reference examples, and the corresponding amide (B. P. -167 C.) is obtained.

B". 1-[allyl-p-xylylacetyl]-piperazines 1-acyl-4-carbethoxypiperazine.-A solution of 24 g. allyl-p-xylylacetylchloride in 50 ml. anhydrous ethyl ether is added dropwise to a well stirred, refluxing mixture of 14.5 g. l-carbethoxypiperazine and 11 g. anhydrous sodium carbonate in 200 ml. anhydrous ethyl ether. After six hours of refluxing, the mixture is treated with 50 ml. H 0 and stirred for two hours. The ether layer is decanted, then dried over anhydrous MgSO The viscous oils are purified by distilling in vacuo to obtain the desired product.

1-acylpiperazine.-The 1-acyl-4-carbethoxypiperazine is refluxed for 24 hours in ethanolic potassium hydroxide to remove the carbethoxy group. The ethanol is separated by reduced pressure distillation. Water is then added egeenrea 5 with stirring: to iiii tl l l thesolidrfiateiial lias dissolved. The resulting} mixture "is extra'ct'e times with'ethy'l ether; dried over anhydrou lL-acyl-piperaziries which are obtained are purified by distilling invacuo'. i M

1-acyl-4-alkylpiperazine. Withtlie exception df uscyr: 4-methylpiperazines, these compounds are prepared as follows: A solutiono'f 0105 mare: 312 ethylchloride; 3.9 propylchloride, etc.) of the appropriate alkyl: halide in 25 ml; anhydrous ethyl ether'is addeddropwiseto a well-stirred, refluxing mixture .of 0.1 'mol- 1'-acylpip,efazine and 0.1 mol anhydrous Na CO in 100 ml. anhydrous ether. After 24 hours of refluxing, themixture is-treated with 10 ml. H and stirred for an additional 4 hours. The ethyl either is separated from the salts by decanting, and then dried aver anhydrous MgjSO 1 -acy l-4-methyli7' ip ri'lzi'rie Methylationfif i-dilylplp i azine with formic acid and formaldehyde by'the' metlfod of Clarke and c wo'rliersg. Ch'ein. Soc; 5594571, 1933), yields the l-acyl-4-methylpiperazine.

EXAMPLE 2 A. Preparation of al lylbenzyla diylchloride is addedin small pieces with stirring Then 80.0 g. of ethyl Sodium, 11.5 g., Y to 250 ml. absolute ethanol. malonate is added slowly to thesodiurnirr alcohol soluns. t m m ir. h 6" j s' i q j s qi db reflux menses g. allvl. Bromide is aaqeaarapwise "The stirring'jandjferi t wa e iiwhhfis. filming is q tinusd' r. PW. 5 Qn P Li alcohol is distilled fr orn lthe r'ea t ion W 1111- 2 is edd dt 1cobls ia qie c e st e is separated and the water layr is extracted with 6 x20 ml. portions of ether. The ester and, ether extracts are combined, dried oyer anhydrous Na SQ and distilled. The fraction "B. P 5 l'1"7"125 "C. is collected and EXAMPLE 3 A. Preparation of allyl-p-fluorobenzylacety[chloride Following the procedure of 2-A except that an equivalent amount of p-fluorobenzylchloride is substituted for the benzylchloride of the reference example, the allyl-pfluorobenzylchloride is obtained (B. P. 108109 C./ 1.0 mm.). The p-fluorobenzylchloride which is used may be prepared by refluxing for 7 hours, a mixture of 0.68 mol p-fluorotoluene, 1.1 mols furfuryl chloride, and 1 g. benzyl peroxide.

B. 1- [allyl-p fluorobenzylacetyl] -piperidine B. 1 [ally l-p-fluorobenzylacetyl -m0rph0line B". 1- [allyl-p-fluorobenzylacetyl] -piperazine Following the procedure of Example 2-13 except that an equivalent amount of p-fluorobenzylchlonide, prepared by refluxing for 7 hours, then distilling in vacuo,

I I v "avatar- The ether extracts' are c'o'm 'rie'd," gSO and distilled, The visc 'us' Afier separating: the ether by distillation, pure componndsare' obtained scribed'above, andin a toluen'e medium, 'Inthe alc'oholmethod it is necessary to'introduce the all'y-l group-intothe molecule first. The a phe'riylethyli-group is thenjn= troduced in similar manner. The alkylation of 50.0 g. diethyl allylmalonate with 46.3' g. a-phenylethyl bromide; 5.75 g; Na an 125 "m1. EtOH yields 60 g; "of diethylallyl-a-phenylethylmalonate, -13: P1 55 -1-"1' 5'-'l20 O.

In the toluene method it is found that by distilling the alcohol formed from the reaction mixture, the groups could be introduced in either order. Diethyl-u-phenylethylmalonate, 52.8 g. is added with stirring to a suspension of 10.8 g. 95% NaOMe in 470 m1. dry toluene.

The MeOH formed is removed by distilling through a short Vigreux column. The column is replaced with a condenser and 15.3 g. allylchloride is added "dropwise ever a period df'two' hours and the mixture refluxed for fourfhours. The reaction mixture is washed with water and ripped of toluene at diminished pressures. The

yield ofdiethyl ally -a-phenylethylmalonate intermediate,

B. PJ 121 C., 11;, 1.5002, amounts to 42 g. (70

percent theoretical).

T diethyl allyl-a-phenylethylmalonate is also repared by reacting 150 g. diethy lallylmalonate'with 4-2-g.

95% NaGMe suspended in 400 ml. dry toluene. The alcohol formed is distilled from the reaction mixture, which is then heated to reflux and g. a-phenylet'hyl bromide added dropwise with stirring over aperiod of two "hours; The'mix'tureisheated and stirred for an additional two hours, filtered through a diatomaceous earth filter'aid to remove NaBr andstripped-of toluene under diminishd'ipressures; The product, B. P. 19.0- 123 C.,'n 1.5020, amounts to 144 g.- I

A mixture" of 60 g.- diethylallyl-bz-phenylethylmalonate intermediate anda solution of 48 g. 'KGH (-85%)-,---l02 ml. EtOH and 48ml. P1 0 is refluxed for twenty-four hours. Most oftlie'alcoliol is removedby distilling on steam bath under slightly diminished, pressures. The due: is; cooled, "treateu'tv'itu m1. HO"fodissolve d; r cidsalt, a dude resulting *solutionmade strongly acid'witir concentrated'nvdroeniorieaeia; THe oiliprodnot 48 g. of crude allyl' a plieiiylethylirfaldnic 'acid;"is decarboxylated by heating in an oil bath maintained at -180 C. for six hours. Thionyl chloride (48 ml.) is added to the resulting acetic acid derivative and the solution heated on a steam bath for two hours and distilled. The acid chloride intermediate can then be used for further condensation.

B. 1 [allyl-a-phenylethylacetyl] -piperidine B. 1 [allyl-a-phenylethylacetyl] -morpholine B". 1 [allyl-a-ph enylethylacetyl] -piperazines Following the procedure of Example l-B, B and B" except that a corresponding amount of allyl-u-phenylacetylchloride is substituted for the allyl-p-xylylacetylchloride of the reference example, the corresponding acetamides are obtained.

EXAMPLE 5 Following the procedure of Example 2-A, B, B and B", except that the corresponding amount of p-methoxybenzyl bromide is substituted for the benzylchloride of the igeference example, the analogous products are obtaine 7 EXAMPLE 6 Following the procedure of Example 1-A and B, except that the corresponding amount of p-fluorobenzylbromide and morpholine is substituted for the p-xylylchloride and piperidine of the reference example, the compound 1-[allyl-p fluorobenzylacetyl]-morpholine (B. P. 153-154" C.) is obtained.

EXAMPLE 7 Following the procedure of Example 1-A and B, except that the corresponding amount of p-fiuorobenzylbromide and pyrrolidine is substituted for the p-xylylchloride and piperidine of the reference example, the

compound 1-[allyl-p-fluorobenzylacetyl]-pyrrolidine (B.

R 140-142" C.) is obtained.

EXAMPLES 8-17 Following the procedures of the examples above, compounds of the formula As has been indicated above, the compounds of the invention may be used as medicinals after compounding in the ordinary manner to form tablets, capsules, elixirs, or any other of the standard dosage unit forms. Following are examples showing the preparation of specific dosage unit forms with the compound l-[allyl-p-xylylacetyll-piperidine taken as the exemplary acetamide.

EXAMPLE 18.-TABLETS Ingredient: Gm. Allyl-p-xylylacetyl-piperidine 0.30 Starch 0.06 Talc 0.018

Carboxymethyl cellulose 1%, q. s.

The acetamide and the starch are put through an mesh screen on the Fitzpatrick-Homoloid machine. They are then thoroughly mixed and the carboxymethylcellulose solution is slowly added while mixing continues. The resulting material is then dried at 60 C., granulated, and returned to the mixer. It is finally screened on talc, then compressed in the usual way.

EXAMPLE l9.ELIXIR Ingredient:

Allyl-p-xylylacetyl-piperidine gms 20 Ethyl alcohol, U. S. P ml Glycerin ml 350 Distilled water, q. s ml 1000 The acetamide is dissolved in the alcohol and the glycerin is added. The mixture is then made to volume with distilled water and filtered.

This invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A compound of the general formula R. OdHcHooN 3: w I

wherein W is a member of the group consisting of hydrogen, halogen, lower alkoxy, and lower alkyl; R is a member of the group consisting of hydrogen and methyl; and Y is a member of the group consisting of methylene, oxygen, and the bond forming a pyrrolidine ring.

2. l-(allylbenzylacetyl) piperidine.

3. 1-(allyl-p-fluorobenzylacetyl) piperidine.

References Cited in the file of this patent UNITED STATES PATENTS 2,717,896 Goldman Sept. 13, 1955 FOREIGN PATENTS 499,298 Canada Jan. 19, 1954 712,343 Great Britain July 21, 1954 OTHER REFERENCES Ramart: Annales de Chemie, vol. 8, series 10 (1927), pp. 268 and 272.-

Zaug et al.: I. A. C. 8., vol. 72, 1950, p. 3005.

Stedmans Medical Dictionary Illustrated, seventeeth ievised edition, The Williams andWilkins (30., Baltimore, 

1. A COMPOUND OF THE GENERAL FORMULA 